title: Recombinant GnRH-p53 protein sensitizes breast cancer cells to 5-fluorouracil-induced apoptosis in vitro and in vivo.
abstract: An ideal approach to treat cancers with dysfunctional p53 tumor suppressor gene is to reinstate p53 functionality by directly using p53 protein as a therapeutic agent. However, this has not been possible because the cells cannot readily internalize the protein. We constructed a fusion protein consisting of gonadotropin-releasing hormone (GnRH-p53) and p53 moieties. The recombinant protein was directly used to treat human breast cancer cells and athymic nude mice bearing breast cancer xenografts, with or without DNA synthesis-arresting agent 5-fluorouracil (5-FU). Treatments of cells from breast cancer cell-lines MDA-MB-231, T47D, or SKBR-3 with GnRH-p53 in combination with 5-FU significantly enhanced p53-activated apoptosis signals, including PUMA expression, BAX translocation to mitochondria, and activated caspase-3. Intratumoral injection of the GnRH-p53 protein inhibited MDA-MB-231 xenograft growth and induced p53-mediated apoptosis in the tumors. Systemic treatment of the tumor-bearing mice via tail vein injection of GnRH-p53 markedly augmented the anticancer efficacy of 5-FU. Substitution of GnRH-p53 with wild type p53 protein had no effect. Recombinant GnRH-p53 is able to function as a surrogate of p53 with regard to its apoptosis-inducing activity. Combination of GnRH-p53 with DNA-damaging drugs may be of important therapeutic value for cancer treatment.
authors.affiliation: Nankai University College of Pharmacy and National Key Laboratory of Medicinal Chemical Biology, 94 Weijin Road, New Life Sciences Bldg A307, Tianjin, 300071, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Zhisong
authors.initials: Z
authors.lastname: Zhang
authors.forename: Zhenwen
authors.initials: Z
authors.lastname: Yan
authors.forename: Li
authors.initials: L
authors.lastname: Chen
authors.forename: Weimin
authors.initials: W
authors.lastname: Deng
authors.forename: Michael
authors.initials: M
authors.lastname: Lotze
authors.forename: Zhou
authors.initials: Z
authors.lastname: Wang
authors.forename: Xinli
authors.initials: X
authors.lastname: Lin
authors.forename: Lu-Yuan
authors.initials: LY
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology* / Q000627:therapeutic use; D007987:Gonadotropin-Releasing Hormone / Q000235:genetics / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D015552:Injections, Intralesional; D051379:Mice; D010446:Peptide Fragments / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000494:pharmacology* / Q000627:therapeutic use; D015398:Signal Transduction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D016159:Tumor Suppressor Protein p53; C509415:p53 protein (325-355), human; D007987:Gonadotropin-Releasing Hormone; D005472:Fluorouracil